JP6050758B2 - Dry powder inhaler and method of operating the same - Google Patents

Description

  The present invention relates to a dry powder inhaler.

  The benefits of inhalation therapy for the treatment of pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis have been recognized for many years. Direct administration of drugs to the respiratory tract minimizes systemic side effects, maximizes lung specificity, and provides rapid onset of action.

  Dry powder inhalers (DPI) are becoming the primary device for delivering therapeutic agents to the patient's respiratory tract. All dry powder inhalation products currently on the market are composed of micronized drugs (aggregates or hybrids) delivered from “passive” dry powder inhalers (DPI). The inhaler is passive in the sense that it relies on the patient's inspiratory effort to disperse the powder into a respirable aerosol.

  Despite popularity and pharmaceutical advantages over other types of inhalers, passive dry powder inhalers typically have relatively poor performance in terms of consistency. In particular, DPI dispenses various doses depending on how the patient uses the device, for example depending on the patient's inhalation efforts.

  Furthermore, the efficiency of DPI is quite poor. In one study comparing the performance of the two most widely prescribed DPIs, only 6% to 21% of the dose dispensed from the device was considered inhalable. Performance improvements for DPI devices are urgently needed from both clinical and product development perspectives. One promising approach to improving DPI performance is to modify the formulation rather than the device itself.

  Conventional formulations for dry powder inhalation aerosols typically contain a micronized drug of sufficiently small particle size to enter the airways and be deposited in the lungs. In order to make these highly cohesive and dispersible very fine particles, so-called “carrier” particles are mixed with the drug particles. These coarse and non-pharmaceutically active (or inert) carrier particles are found in almost all dry powder inhaler products currently on the market. The carrier particles serve to enhance the fluidization of the drug because the drug particles are usually too small to be effectively affected by the air flow through the inhaler. Thus, the carrier particles improve dose uniformity by acting as a diluent or bulking agent in the formulation.

  Although these carrier particles, generally about 50-100 microns in size, improve the performance of dry powder aerosols, the performance of dry powder aerosols remains relatively low. For example, only about 30% of the drug in a typical dry powder aerosol formulation will be delivered to the target site, and in many cases even less. Large amounts of drug are not released from these conventional carrier particles, and because of the relatively large size of the carrier relative to the drug, the drug is deposited in the patient's throat and mouth, where it is desired. It may have unexpected side effects.

  Dry powder formulations typically consist of micronized drug particles (aerodynamic diameter typically 1-5 μm) and larger inert carrier particles (typically 63-90 μm diameter lactose). Hydrate) and a binary mixture. Drug particles are subject to cohesion with other drug particles and adhesion to carrier particles (mainly due to van der Waals forces), but must be overcome to effectively disperse the powder and increase lung deposition efficiency Is the force between these fine particles. The energy used to overcome the interparticle force is provided by the patient's inspiration when the patient uses the inhaler. Aerodynamic forces involve the powder to disaggregate, but fluctuations in the patient's inhalation effort (such as those resulting from airway fibrosis or obstruction) can significantly affect drug dispersion and deposition and depend on inhaler flow rate Bring sex. Needless to say, there is a need for an improved dry powder formulation using new carrier particles to maximize the safety and efficacy profile of current DPI inhalers.

  Drug substances (APIs), also called drugs, typically make up less than 5% (% w / w) of the formulation, with lactose accounting for the majority of the dose. The use of carrier lactose is to prevent aggregation of drug particles due to agglomeration forces, primarily van der Waals forces arising from the instantaneous dipole moment between adjacent drug particles. Due to the small size of the drug particles, the resulting cohesive force is very strong and does not easily dissociate with the aerodynamic force provided by inhalation, which has poor fluidity and eventually deposits behind the throat Occurs. By using a binary mixture, the drug will instead adhere to the carrier particles, and the carrier particles are larger in size, making it easier to be entrained in the air flow generated during patient inhalation and making the API mesh Carrying towards the carrier particles impact the mesh; the force of the impact is often sufficient to pull the drug particles away from the carrier, dispersing the drug particles in the air stream and into the lungs Allows the deposition of the particles. In some cases, a collision with the inner wall of the inhaler is important. However, the majority of the API remains bound to a carrier that has been displaced without effectively colliding with the mesh and generating insufficient force to disperse the drug particles from the surface. APIs that are not dissociated from these carriers, along with drugs attached to carrier particles that slip through without contacting the mesh, are often deposited behind the throat by inertial collisions, resulting in significant side effects in the throat.

  Over the past 20 years, a great deal of search for optimal properties of DPI formulations has been conducted. DPI formulations improve the redispersion of agglomerated drug particles and reduce the dosage variation by using large inert carrier particles to be hybridized with small micronized (<5 micron) drug particles. I needed it. Without carrier particles, the micronized drug remains agglomerated and almost all is inhaled only to the throat swallowing the drug and does not reach the intended target. There are many studies investigating these carrier particles, but alterations in the physiochemical properties (size, shape, crystallinity, surface microstructure, roughness, etc.) of the carrier particles have implications for DPI performance. It has not produced any improvement. In addition, these carrier particles (lactose in the United States) are also responsible for batch-to-batch variations in DPI performance. One of the best-studied properties of carrier particles is carrier particle size. During 20 years, a rule of thumb was established that increasing the carrier particle size resulted in a decrease in DPI performance. FIG. 1 shows some examples from previous literature that showed that increasing the carrier particle size in the DPI formulation resulted in performance degradation.

  In some conventional DPIs, carrier particles can exit the inhaler and may even be intended to exit. As a result, the carrier particles must be inert, and in the United States the FDA limits the carrier particle material to lactose. Thus, alternative carriers that can be more carefully selected based on the hygroscopic nature of the carrier (eg, desiccant material) and the surface interaction between the carrier and drug (eg, the nature of the drug and carrier as an acid or base) There is a need for advanced formulation techniques involving particulate materials. Therefore, it may be desirable to provide a DPI that is completely devoid of carrier particles in order to be able to avoid the FDA limitation of lactose as the carrier material.

Nasal delivery is used for the treatment of various diseases such as allergic rhinitis, as well as drug delivery for systemic or CNS effects.
Both powder and liquid nasal delivery systems are currently on the market. Liquid delivery techniques have utilized techniques derived from spray pumps or pressurized metered dose inhalers (pMDIs) for rapid injection of formulations into the nasal cavity. In general, nasal formulations are solution or suspension based formulations that require a solvent or stabilizer. These are typically administered as a spray. Metered sprays and pump sprays have several disadvantages, such as:
Priming is necessary to ensure “dose uniformity”. Complex and expensive design with many device parts of different materials. Difficult to manufacture the device. Not stable ・ Insufficient control over the site of deposition in the nasal cavity ・ Product deposition often concentrates on certain tissues, causing irritation to the area, but not elsewhere in the nasal cavity -The variation in dosing to the target tissue is significant because the positioning of the device in use is important and strongly dependent on the patient's usage.

  DPI device technology has been applied to nasal delivery based primarily on locally acting drugs. The formulation has significant advantages such as stability and dose delivery. This can be particularly advantageous for biologics and drugs that require systemic plasma concentrations. Included in the system is a modified dry powder inhaler (developed for oral inhalation aerosol delivery) with a “nostral piece” instead of a “mouthpiece”. Such a device is driven by nasal inhalation. This device is also a known concept from DPI technology: reservoir dry powder with metering mechanism-or capsule-based device that requires a puncture mechanism and special loading procedures before and after use Apply. These device concepts are similar problems that arise when using DPI for pulmonary delivery: complicated formulation and high resistance to air flow make it difficult to achieve sufficient nasal dose delivery I have inherited that.

  In order to solve these device resistance problems, insufflators have been designed that “blow” the drug powder formulation into the nostril. From a mechanical point of view, this device is “bulky” and has limited portability and cannot be manipulated with caution. In addition, the device has the same disadvantages of variability and local deposition during use of the spray system.

  The present invention relates generally to dry powder inhalation aerosols and to a method of delivering a drug or therapeutic agent to a patient. More specifically, the present invention is designed for direct application of active agents to patients, utilizing the novel working sphere design and associated inhalers to take advantage of these unique properties. The In some embodiments, the present invention further utilizes the high performance of powder dispersions at low flow rates so that the powder can be successfully delivered to various regions of the nasal cavity.

  According to one aspect, a dry powder inhaler includes an inlet channel through which air enters the inhaler and a chamber that receives air from the inlet channel, the actuator having a powdered drug attached thereto And a chamber that is sized and shaped. The dry powder is a holding member disposed at the end of the chamber opposite the inlet channel, which allows air and powdered drug to pass through and an actuator is provided to the holding member. And a retention member having one or more openings sized to prevent passage therethrough and an outlet channel through which air and powdered medicament exit the inhaler for delivery to the patient. The inhaler geometry is such that a flow profile that vibrates the actuator is generated inside the chamber so that the powdered drug is detached from the actuator surface and entrained in the air and through the outlet channel. To be delivered to the patient. In some embodiments, the cross-sectional area of the flow path through the inhaler is increased by one step at the chamber inlet. At the chamber inlet, the chamber diameter can be at least 1.5 times the inlet channel diameter. The inlet channel can comprise a tapered tube. The outlet channel can comprise a tube whose cross-sectional area varies along its length. In some embodiments, the outlet channel is included in a mouthpiece adapted to be placed in the patient's mouth. In some embodiments, the outlet channel is included in a nasal adapter adapted to fit the patient's nostril.

  The dry powder inhaler further comprises one or more bypass channels that receive makeup air from outside the inhaler and deliver the makeup air to the patient without passing through the chamber. In some embodiments, the inlet channel is a first inlet channel and the chamber is a first chamber, and the dry powder inhaler further comprises a second inlet channel and a second chamber. In some embodiments, air and powdered medicament exiting the first and second chambers are delivered to the outlet channel. In some embodiments, the outlet channel is a first outlet channel, the dry powder inhaler further comprises a second outlet channel, and the air and powdered drug exiting the first chamber is the first outlet channel. Air and powdered drug that is delivered to the flow path and exits the second chamber is delivered to the second exit flow path. The first and second chambers may be the same size. The dry powder inhaler may be separable so that a capsule containing the actuator can be inserted into the chamber. The dry powder inhaler may further include a mechanism for puncturing the sealing portion at the capsule end. The air flow through the inhaler can be driven by the patient's inspiratory effort.

In some embodiments, the dry powder inhaler is combined with an actuator. The actuator may be made of expanded polystyrene. The actuator can have a density of 0.001 to 0.50 g / cm ³ . The actuator can have a diameter of at least 1000 microns. The actuator can have a diameter of 1000-6000 microns. In some embodiments, a combination of drugs is attached to the actuator. In some embodiments, the dry powder inhaler comprises a plurality of chambers disposed on a rotating element for selectively aligning any of the chambers with the outlet flow path. ing.

  According to another aspect, a method is a dry powder inhaler comprising an inlet channel, a chamber, and an outlet channel, the chamber containing an actuator, and one or more powdered drugs are activated. Obtaining a dry powder inhaler attached to the outer surface of the vessel; inhalation is performed through the outlet channel to allow air to flow into the inlet channel, pass through the chamber, and pass through the outlet chamber The air flow further oscillates the actuator to expel the powdered drug from the surface of the actuator and is entrained in the air flow and conveyed through the outlet channel. In some embodiments, the method includes separating the portion of the inhaler comprising the chamber and the outlet flow path, loading the actuator into the chamber, and reengaging the two portions of the inhaler. Further comprising the step of: A combination of powdered drugs may be attached to the actuator. In some embodiments, the dry powder inhaler comprises at least two chambers that contain at least two actuators having a drug attached thereto, and the air flow should be inhaled by vibrating each actuator. Expel powdered drugs. The same powdered drug may be attached to at least two actuators. In some embodiments, the at least two actuators may have different powdered drugs attached thereto.

FIG. 3 shows some examples from existing literature showing the relationship between carrier particle size in DPI formulations and DPI performance. The figure explaining the specific principle utilized by embodiment of this invention. The figure explaining the specific principle utilized by embodiment of this invention. The figure explaining the specific principle utilized by embodiment of this invention. FIG. 5 shows relative adhesion and withdrawal forces as a function of carrier size. 1 is a perspective view of a dry powder inhaler (DPI) according to an embodiment of the present invention. FIG. FIG. 4B is a side view of the DPI of FIG. 4A. 4D is a cross-sectional view of the DPI of FIG. 4A. 4B illustrates the DPI of FIG. 4A in operation. FIG. 6 is a perspective view of a DPI according to another embodiment. FIG. 5B is a cross-sectional view of the DPI of FIG. 5A. FIG. 3 is a cross-sectional view of an alternative chamber portion according to an embodiment of the invention. FIG. 6 is a cross-sectional view of a DPI according to another embodiment. FIG. 6 is a perspective view of a chamber portion according to another embodiment. FIG. 8B is a cross-sectional view of the chamber portion of FIG. 8A. FIG. 6 illustrates an alternative arrangement for connecting a plurality of chambers to one or more outlet channels according to an embodiment of the invention. FIG. 6 illustrates an alternative arrangement for connecting a plurality of chambers to one or more outlet channels according to an embodiment of the invention. FIG. 6 is a perspective view of a chamber portion according to another embodiment. FIG. 9B is a cross-sectional view of the chamber portion of FIG. 9A. FIG. 9B is a cross-sectional view of a DPI using the chamber portion of FIG. 9A, according to one embodiment of the invention. The figure which shows the cartridge by one Embodiment. FIG. 11 illustrates the steps of a method for producing the cartridge of FIG. 10 according to one embodiment. FIG. 11 illustrates additional steps of a method for producing the cartridge of FIG. 10 according to one embodiment. The figure which shows the continuous type inhaler by one Embodiment of this invention. The figure which shows the continuous inhaler of FIG. 13 after loading.

  While the manufacture and use of various embodiments of the present invention are discussed in detail below, it should be understood that the present invention provides a number of applicable inventive concepts that may be embodied in a wide variety of specific situations. Is. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention, and do not delimit the scope of the invention.

  Any embodiment discussed herein can be implemented for any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, the compositions of the present invention can be used to accomplish the methods of the present invention.

  It will be appreciated that the specific embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be used in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.

  All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains. All publications and patent applications are hereby incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated.

  In order to facilitate understanding of the present invention, some terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the art to which this invention belongs. Terms such as “a”, “an” and “the” are not intended to refer to only the singular, but are used for illustration. Includes the entire collection of possible examples. The terminology herein is used to describe specific embodiments of the invention, but its use does not delimit the invention, except as outlined in the claims. .

  The use of the term “a” or “an” when used with the term “comprising” in at least any of the claims or specification, It can also mean “one”, but the words are also “one or more”, “at least one”, and “one or more”. It also coincides with the meaning of “more than one)”. The use of the term “or” in the claims is expressly stated to refer to only one of the options or unless the option is mutually exclusive, May support only one and the definition of “and / or” and / or “and / or”. Is used to mean Throughout this application, the term “about” encompasses the inherent variation in error in which a value relates to the device, the method being used to determine the value, or the variation present in the study object. Used to indicate

  As used herein and in the claims, the term “comprising” (and any form thereof, eg, “comprise” and “comprises”), “having ( "having" (and any form thereof, such as "have" and "has"), "including" (and any form thereof, such as "includes" and " "Include"), or "containing" (and any form thereof, such as "contains" and "contain") is inclusive or open-ended Does not exclude additional unlisted elements or method steps.

  The term “or combinations thereof” as used herein refers to any permutation and combination of items listed prior to the term. For example, “A, B, C, or combinations thereof” refers to the following: A, B, C, AB, AC, BC, or ABC, and further BA, CA, CB if order is important in a particular situation , CBA, BCA, ACB, BAC, or CAB. Continuing with this example, clearly included are combinations including one or more items or term repetitions, such as BB, AAA, MB, BBC, AAABCCCCC, CBBAAA, CABABB, and the like. One of ordinary skill in the art will understand that there is generally no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

  In the description that follows, like parts may be indicated using the same reference numerals throughout the specification and drawings, respectively. Drawings are not necessarily to scale, and certain features may be shown exaggerated on scale, or may be shown in a somewhat generalized or schematic form for clarity and clarity.

  A working sphere is a large bead or other bearing-type object constructed of a low density mechanical elastic material that can be applied to any suitable technique such as injection molding, compression molding, casting material onto the core. Can be prepared for use. The working sphere may be made from ionomer resin, polyurethane, silicone, and other materials. The working sphere has a generally spherical outer surface, while it can have multiple indentations or other depressions or protrusions to optimize aerodynamic properties and improve retention of the active agent. The working sphere is utilized in the sense of providing a medium for attaching the active agent, thus releasing the active agent upon introduction of force or inertia.

An actuator is a bead or other bearing-type object to which a drug is attached and which vibrates in response to air flow. The working sphere is a kind of actuator.
Drug substance; Active agonist:
Active pharmaceutical ingredients (APIs), ie active agents, include analgesic anti-inflammatory agents such as acetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, glycol salicylate, l-menthol, camphor, mefenamic acid, flufenam. Acid (flufenamic acid), indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxene, pranoprofen, fenoprofen, sulindac, fenbufen, cridanac, flurbiprofen, indoprofen, protiidic acid (protiid) , Fenthiazac, Tolmethine, Tiaprofenic acid, Bendazac, Bufexamac, Piroxicam, Phenylbutazone, Oxyfenbu Dzong, clofezone, pentazocine, and the like Mepirizoru.

  Drugs that act on the central nervous system, such as sedatives, hypnotics, anxiolytics, analgesics, and anesthetics such as chloral, buprenorphine, naloxone, haloperidol, fluphenazine, pentobarbital, phenobarbital, secobarbital, amobarbital, Cyclobarbital (codebarbital), codeine, lidocaine, tetracaine, dichronin, dibucaine, cocaine, procaine, mepivacaine, bupivacaine, etidocaine, prilocaine, benzocaine, fentanyl, nicotine and the like. Local anesthetics such as benzocaine, procaine, dibucaine, lidocaine and the like.

  Antihistamines or antiallergic agents such as diphenhydramine, dimenhydrinate, perphenazine, triprolysine, pyrilamine, chlorcyclidine, promethazine, carbinoxamine, tripelenamine, bromopheniramine, hydroxyzine, cyclidine, meclizine, chlorprenalin, terfenadine, chlor Phenylamine, etc. Antiallergic agents such as antazoline, metapyrylene, chlorpheniramine, pyrilamine, pheniramine and the like. Decongestants such as phenylephrine, ephedrine, naphazoline, tetrahydrozoline and the like.

  Antipyretics such as aspirin, salicylamide, non-steroidal anti-inflammatory drugs and the like. Antimigraine agents such as dihydroergotamine, pizotirin and the like. Acetonide anti-inflammatory agents such as hydrocortisone, cortisone, dexamethasone, fluocinolone, triamcinolone, medrizone, prednisolone, fullland lenolide, prednisone, harsinonide, methylprednisolone, fludrocortisone, corticosterone, parameterzone, betamethazone, ibuprofena Profen, fenbufen, flurbiprofen, indoprofen, ketoprofen, suprofen, indomethacin, piroxicam, aspirin, salicylic acid, diflunisal, methyl salicylate, phenylbutazone, sulindac, mefenamic acid, sodium meclofenamic acid, tolmethine and the like. Muscle relaxants such as tolperisone, baclofen, dantrolene sodium, cyclobenzaprine.

  Steroids such as androgenic steroids such as testosterone, methyltestosterone, fluoxymesterone, estrogens such as conjugated estrogens, estrogen esters, estropipate, 17-β estradiol, 17-β estradiol, 17-β valerate, Ekiline, mestranol, estrone, estriol, 17β ethinylestradiol, diethylstilbestrol, progesterone agent such as progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chlormadinone, etisterone, medroxyprogesterone acetate, caproic acid Hydroxyprogesterone, ethinodiol diacetate, nor Chinodoreru, 17-alpha-hydroxyprogesterone, dydrogesterone, dimethisterone, ethynyl Lisbon Nord (ethinylestrenol), norgestrel, demegestone, promegestone, and megestrol acetate.

  Respiratory drugs, such as theophylline and beta2-adrenergic drugs, such as albuterol, terbutaline, metaproterenol, ritodrine, carbuterol, fenoterol, quinterenol, limiterol, salmefamol, soterenol, tetroquinol (Tetraquinol), tacrolimus and the like. Sympathomimetic agents such as dopamine, norepinephrine, phenylpropanolamine, phenylephrine, pseudoephedrine, amphetamine, propylhexedrine, arecoline and the like.

  Antimicrobial agents such as antibacterial agents, antifungal agents, antimycotic agents and antiviral agents; ie, tetracyclines such as oxytetracycline, penicillins such as ampicillin, cephalosporins, For example, cephalothin, aminoglycosides, such as kanamycin, macrolides, such as erythromycin, chloramphenicol, iodide, nitrofurantoin, nystatin, amphotericin, fradiomycin, sulfonamides, pyrrololnitrin, clotrimazole, itraconazole, Miconazole, chloramphenicol, sulfacetamide, sulfamethazine, sulfadiazine, sulfamerazine, Antiviral drugs such as idoxuridine; clarithromycin; and other anti-infective drugs including nitrofurazone.

  Antihypertensive agents such as clonidine, α-methyldopa, reserpine, silosingopine, resinamine, cinnarizine, hydrazine, prazosin and the like. Diuretics for hypertension, such as chlorothiazide, hydrochlorothiazide, bendroflumethazide, trichlormethiazide, furosemide, tripamide, methylcrothiazide, penfluzide, hydrothiazide, spironolactone, metolazone. Cardiotonics, such as digitalis, ubidecalenone, dopamine, and the like. Coronary vasodilators such as organic nitrates such as nitroglycerin, isosorbitol dinitrate, erythritol tetranitrate and pentaerythritol tetranitrate, dipyridamole, dirazep, trapidil, trimetazidine and the like. Vasoconstrictors such as dihydroergotamine, dihydroergotoxin and the like. β-blockers or antiarrhythmic agents such as timolol, pindolol, propranolol and the like. Fluids for body fluids, for example, misoprostol, which is a natural and synthetic prostaglandin, such as PGE1, PGE2α, PGF2α, and PGE1 analogs. Antispasmodic agents such as atropine, methanthelin, papaverine, cinnamedrine, methoscopolamine and the like.

  Calcium antagonists and other cardiovascular agents such as captopril, diltiazem, nifedipine, nicardipine, verapamil, bencicurn, ifenprodil tartrate, molsidomine, clonidine, prazosin, and the like. Anticonvulsants such as nitrazepam, meprobamate, phenytoin and the like. Agents for dizziness, such as isoprenaline, betahistine, scopolamine. Tranquilizers such as reserpine, chlorpromazine, and benzodiazepine anxiolytics such as alprazolam, chlordiazepoxide, chlorazepate, halazepam, oxazepam, prazepam, clonazepam, fluazepam, zepamum, zepamum, zepamum, zepamom,

  Antipsychotics such as phenothiazines such as thiopropazate, chlorpromazine, triflupromazine, mesoridazine, piperacetazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, and other major tranquilizers ( tranquilizers, such as chlorprothixene, thiothixene, haloperidol, bromperidol, loxapine and morindon, and agents used at low doses in the treatment of nausea, vomiting, and the like.

  Drugs for Parkinson's disease, spasticity, and acute muscle spasm, such as levodopa, carbidopa, amantadine, apomorphine, bromocriptine, selegiline (deprenyl), trihexyphenidyl hydrochloride, benztrobin methanesulfonate, procyclidine hydrochloride, baclofen, diazepam, dantrolene, Such. Respiratory agents such as codeine, ephedrine, isoproterenol, dextromethorphan, orciprenaline, ipratropium bromide, chromglycic acid, and the like. Non-steroidal hormones or antihormones such as corticotropin, oxytocin, vasopressin, salivary hormone, thyroid hormone, adrenal hormone, kallikrein, insulin, oxendron, etc.

  Vitamins such as vitamins A, B, C, D, E, and K and their derivatives, calciferol, mecobalamin, etc. for use in dermatology. Enzymes such as lysozyme, urokinase, etc. Herbal medicine or herbal crude extract, such as aloe vera, etc.

  Antitumor agents such as 5-fluorouracil and its derivatives, krestin, picibanil, ancitabine, cytarabine, and the like. Antiestrogens or antihormonal agents such as tamoxifen or human chorionic gonadotropin. Miotic drugs, such as pilocarpine.

  Cholinergic agents such as choline, acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, muscarin, arecoline, and the like. Antimuscarinic or muscarinic cholinergic blockers such as atropine, scopolamine, homatropin, metoscopolamine, homatropine methylbromide, methanelin, cyclopentrate, tropicamide, propantheline, anisotropin, dicyclomine, eucatropin, and the like.

  Mydriatics such as atropine, cyclopentrate, homatropine, scopolamine, tropicamide, eucatropine, hydroxyamphetamine, etc. Mental energizers such as 3- (2-aminopropyl) indole, 3- (2-aminobutyl) indole, and the like.

  Antidepressants such as isocarboxazide, phenelzine, tranylcypromine, imipramine, amitriptyline, trimipramine, doxepin, desipramine, nortriptyline, protriptyline, amoxapine, maprotiline, trazodone, and the like.

Antidiabetics such as insulin, and anticancer agents such as tamoxifen, methotrexate, and the like.
Appetite suppressants, such as dextroamphetamine, methamphetamine, phenylpropanolamine, fenfluramine, diethylpropion, mazindol, phentermine, and the like.

Antimalarials such as 4-aminoquinoline, alpha aminoquinoline, chloroquine, pyrimethamine, and the like.
Anti-ulcer agents such as misoprostol, omeprazole, enprostil, etc. Anti-ulcer drugs such as allantoin, aldioxa, alcloxa, N-methylscopolamine methylsulfate, and the like. Anti-diabetic drugs such as insulin.

  Anticancer agents such as cisplatin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, teniposide, taxol, colchicine, cyclosporin A, phenothiazines or thioxanthones, Such.

  For use with vaccine agents, one or more antigens, such as natural antigens, heat-killer antigens, inactivated antigens, synthetic antigens, peptide antigens and even T cell epitopes (eg GADE, DAGE, MAGE) Etc., etc.

  Exemplary therapeutic or active agents include drugs having a molecular weight of 40-1100, such as: hydrocodone, Lexapro®, Vicodin®, Effexor®, Paxil®, Wellbutrin (registered trademark), Bextra (registered trademark), Neurotin (registered trademark), Lipitor (registered trademark), Percocet (registered trademark), oxycodone, Valium (registered trademark), naproxen, tramadol, Ambien (registered trademark), Oxycontin ( (Registered trademark), Celebrex (registered trademark), prednisone, Celexa (registered trademark), Ultracet (registered trademark), Protonix (registered trademark), Soma (registered trademark), atenolol, lisinopril, ortab (registered trademark), Darvocet (registered trademark), Cipro (registered trademark), Levaquin (registered trademark), Ativan (registered trademark), Nexium (registered trademark), cyclobenzaprine, Ultram (registered trademark), alprazolam, trazodone, Norvasc (R), Biaxin (R), Codeine, Clonazepam, Toprol (R), Zithromax (R), Diovan (R), Skelaxin (R), Klonopin (R), Lorazepam, Depakote Registered trademark), diazepam, albuterol, Topamax (registered trademark), Seroquel (registered trademark), amoxicillin, Ritalin (registered trademark), methadone, Augmentin (registered trademark) ), Zetia (registered trademark), cephalexin, Prevacid (registered trademark), Flexeril (registered trademark), Synthroid (registered trademark), promethazine, phentermine, metformin, doxycycline, aspirin, Remeron (registered trademark), metoprolol, amitriptyline, Advair (Registered trademark), ibuprofen, hydrochlorothiazide, Crestor (registered trademark), acetaminophen, Concerta (registered trademark), clonidine, Norco (registered trademark), Elavil (registered trademark), Abilify (registered trademark), Risperdal (registered trademark) , Mobic®, ranitidine, Lasix®, fluoxetine, Coumadin®, diclofenac, hydroxy Shidin, Phenergan®, Lamictal®, verapamil, guaifenesin, Acifex®, furosemide, Entex®, metronidazole, carisoprodol, propoxyphene, digoxin, Zanaflex®, Clindamycin, Tripeptal®, Buspar®, Keflex®, Bactrim®, Dilantin®, Flomax®, Benical®, Baclofen, Endocet ( (Registered trademark), Avelox (registered trademark), Lotrel (registered trademark), Internal (registered trademark), Provigil (registered trademark), Zantac (registered trademark), fentanyl, remarin (R), penicillin, Claritin (R), Reglan (R), enalapril, Tricor (R), methotrexate, Pravachol (R), amiodarone, Zelnorm (R), erythromycin, Tegretol (R) ), Omeprazole and meclizine.

Other active agonists include those listed as BCS class II agonists.
The above-mentioned active agents can be used in combination as necessary. Furthermore, the drug may be used in free form, or in the form of a salt with a suitable acid or base if it can form a salt. If the drug has a carboxyl group, an ester of the drug may be used.

  2A-2C illustrate specific principles utilized by embodiments of the present invention. In FIG. 2A, the actuator 201 is in the chamber 202. As will be described in more detail below, the powdered drug is attached to the actuator 201. The powdered drug may be in a pure form or may be attached to carrier particles. The drug can be coupled to the actuator 201 by van der Waals forces, which can include a combination of permanent dipoles, induction dipoles and instantaneous dipoles. Other coupling mechanisms may be used as an alternative or in addition. For example, the adhesion force can arise from van der Waals forces, electrostatic interactions, physical interactions, capillary interactions, or combinations thereof. Air 203 is drawn into the chamber 202 through the inlet channel 204. Since the inlet channel 204 has a cross-sectional area smaller than the size of the actuator 201, the actuator 201 cannot enter the inlet channel 204. A holding member 205 at the other end of the chamber 202 prevents the actuator 201 from exiting that end of the chamber 202. The holding member 205 can be, for example, a mesh or grid such that air can flow through the holding member, but the actuator 201 is held inside the chamber 202. In some embodiments, the retention member 205 can define an opening that is about 250 microns wide to prevent passage of particles larger than about 250 microns. In other embodiments, the retention member 205 can define an opening that is about 500 microns wide to prevent passage of particles larger than about 500 microns. Other sieve sizes are possible. In some embodiments, the retention member 205 may have a closed area of less than 50%, and in other embodiments, the closed area may be greater than 50%. When the size of the actuator 201, chamber 202, and inlet channel 204 are properly selected, the flow of air through the system causes the actuator 201 to vibrate rapidly in a substantially axial direction of the flow.

Actuators useful in embodiments of the present invention and illustrated by actuator 201 may be spherical or nearly spherical, but have other shapes as well, for example, elliptical, polygonal, or other shapes You can also. The actuator may be smooth or have a recess, indentation, protrusion, or other surface feature. The actuator can be any suitable material, such as a polymer such as polystyrene, polytetrafluoroethylene, or another type of polymer, polyurethane, silicon, silicone glass, silica gel, other glass, other gel, or another type of material. Alternatively, it can be made of a combination of materials. The actuator may be made of a biodegradable material or a non-biodegradable material. Many other types of materials or combinations of materials may be used. The actuator has a relatively low density, for example 0.001-0.5 g / cm ³ , or preferably 0.001-0.12 g / cm ³ , or more preferably 0.001-0.04 g / cm ^3. Can have. The actuator may be of any suitable size that is compatible with the chamber holding the actuator therein. For example, the actuator is 500-25000 microns (0.5-25 mm), preferably 1000-10000 microns (1.0-10.0 mm), more preferably 1000-6000 microns (1.0-6.0 mm). Can have a diameter or other maximum dimension. The actuator can be manufactured by any suitable manufacturing method depending on the material of the actuator. For example, the actuator can be manufactured by molding, extruding, milling, spray drying, polymer imprinting, or other manufacturing methods or combinations of manufacturing methods. In some embodiments, the actuator can have a mass of less than 10.0 mg, such as less than 5.0 mg, or less than 2.5 mg. In other embodiments, the actuator can have a mass greater than 0.001 mg, such as greater than 0.1 mg, or greater than 0.5 mg. In some embodiments, the actuator can have a mass of 0.001 mg to 10.0 mg, such as 0.1 mg to 5.0 mg, or 0.5 mg to 2.5 mg.

  FIG. 2B illustrates the formation of the recirculation vortex 206 in the empty chamber 202. As the flow enters the chamber 202, the flow leaves the inner wall of the system at the corner of the extension, where the inlet channel 204 opens toward the chamber 202, and reattaches downstream. At the corner of this extension, a portion of the incoming flow deviates from the main flow and becomes trapped in the corner 207 of the chamber 202 as a recirculation vortex 206. If the actuator 201 is introduced into the chamber 202, the flow can be more complex. The end result is that the actuator 201 vibrates rapidly substantially along the axis of the chamber 202. The actuator 201 can also rotate in three dimensions at maximum.

  FIG. 2C is a multiple exposure photograph of an actual system in which the actuator 201 is oscillating. Surprisingly, it has been found that the actuator 201 has little contact with the walls or ends of the chamber 202 during vibration. However, the vibration of the actuator 201 is sufficient as a scale for driving out the powdered medicine from the surface of the actuator 201.

This is due in part to the relatively large size of the actuator 201 compared to the carrier particles used in conventional inhalers. The adhesion force to fix the powdered drug on the carrier particles is;
F _adhesive = (A _H d ₁ d ₂ ) / {12D ² (d ₁ + d ₂ )}
Where A _H is the Hamaker constant, typically in the range of 10 ⁻¹⁹ J, and D is the interparticle distance, generally 4 angstroms (10 ⁻¹⁰ m ), D ₁ and d ₂ are the diameters of the drug and carrier particles, respectively. The separation force generated by the vibration of the actuator 201 is generally proportional to the cube of the diameter of the actuator 201. Thus, for large actuators, it is possible to generate a detachment force that exceeds the adhesion force, as shown in region 301 in FIG.

According to embodiments of the present invention, these principles are utilized to produce an inhaler with improved performance.
Inhaler Embodiment FIG. 4A shows a perspective view of a dry powder inhaler (DPI) 400 according to an embodiment of the present invention. The DPI 400 includes a mouthpiece 401 through which the outlet channel 402 passes. The DPI 400 further includes a chamber portion 403 engaged with the mouthpiece 401. The DPI 400 may further include a holding mechanism 404 for fixing the mouthpiece 401 and the chamber portion 403 together. The coupling mechanism 404 may be detachable to allow the mouthpiece 401 and chamber portion 403 to be separated and recombined, for example, for loading the DPI 400. Any suitable coupling mechanism can be used. 4B shows a side view of DPI 400, and FIG. 4C is a cross-sectional view of DPI 400 showing some internal details.

  The chamber portion 403 of the DPI 400 includes an inlet channel 405 that communicates with the chamber 406. Optionally, the inner surface of chamber 406 may be provided with ridges or other surface features to minimize the area where an actuator contained within chamber 406 contacts the wall. The chamber 406 has a larger cross-sectional area than the inlet channel 405, and the air flow path through the DPI 400 is increased by one step at the inlet / outlet 407 of the chamber 406. Chamber 406 is of a size and shape that includes an actuator to which a powdered drug is deposited. The DPI 400 further includes a holding member 407 downstream of the chamber 406. The retention member 407 includes an opening (not visible in FIG. 4C) sized to allow air to flow through the retention member 408 but the actuator to be retained within the chamber 406. Yes. The retaining member may be, for example, a mesh or grid installed across the end of the chamber 406 or the outlet channel 402.

  FIG. 4D illustrates the DPI 400 in operation. In FIG. 4D, actuator 409 has been loaded into chamber 406. The actuator 409 cannot pass through the inlet channel 405 and cannot pass through the opening of the retaining member 408, and is therefore large enough to hold the actuator 409 inside the chamber 406. is there. The actuator 409 may be spherical or nearly spherical, but is not a requirement. Since the actuator 409 does not exit the chamber 406, i.e., does not contact the patient, the actuator need not be made of lactose and is more flexible in selecting the material of the actuator 409 than for the carrier particles of a conventional inhaler. The sex becomes higher. The actuator 409 can be made of, for example, polystyrene, polytetrafluoroethylene (PTFE, also known as Teflon), silicone glass, silica gel, glass, or other suitable material. In some embodiments, the actuator 409 may be made of a biodegradable material.

  Powdered drug particles 410 (shown in exaggerated size in FIG. 4D) are attached to the actuator 409. The patient puts the mouthpiece 401 in his mouth and inhales. The patient's inspiratory effort draws air 411 into the inlet channel 405. As described above, the actuator 409 oscillates substantially along the axial direction of the flow path so that the particles 410 are ejected from the surface of the actuator 409 and the particles are entrained in the flow. The expelled particle 410 passes through the holding member 408, passes through the outlet channel 402, exits the DPI 400, and is inhaled by the patient. The exit channel 402 includes a ridge or groove (similar to a swivel in a gun barrel) to help direct the drug flow into a straight path as it exits the device. May be. The actuator 409 can vibrate many times with one inhalation, and may vibrate several hundred times. The vibration frequency is typically 1-1000 Hz, preferably 25-150 Hz, although other frequencies may occur. The vibration can also produce an audible sound that can provide audible feedback to the patient using DPI to indicate that the drug is being delivered.

These vibrations give the actuator more force than is applied to the lactose carrier particles upon impact in a conventional inhaler.
Inhalers that are driven solely by the patient's inspiratory effort are known as passive inhalers. It will be appreciated that the present invention may be embodied in a passive inhaler or in an inhaler that uses at least partially another energy source to propel airflow. .

Many variations are possible within this basic framework. FIG. 5A shows a perspective view of a DPI 500 according to another embodiment. The DPI 500 includes several features similar to those of the DPI 400 described above, including a mouthpiece 501 that includes an outlet channel 502. The DPI 500 further includes a bypass channel 503 connected to the sheath channel 504. FIG. 5B is a cross-sectional view of DPI 500 showing the internal configuration of bypass channel 503 and sheath channel 504. The makeup air 505 is drawn into the bypass channel 505, passes through the sheath channel 504, and reaches the patient without passing through the chamber 506. A bypass flow path may be provided to reduce the flow resistance of the DPI 500 while still providing sufficient air flow through the chamber 506 for delivering powdered medication to the patient. For example, in a direct comparison, a device without a bypass channel is about 0.140 (cmH ₂ O) ₂ ^{. 5} / L min- ¹ flow resistance, resulting in a discharge rate of about 46 L min- ¹ with a pressure drop of 4 kPa via an inhaler, while having a bypass flow path The device is approximately 0.061 (cmH ₂ O) ₂ ^{. 5} / L min has a flow resistance of ^-1, the result it was determined that the discharge amount of about 105L min ^-1 with a pressure drop of 4kPa over the inhaler.

  In another variation, FIG. 6 shows a cross-sectional view of another example chamber portion 601. Chamber portion 601 is similar to chamber portion 403 described above, but is not a cylindrical inlet flow path, but chamber portion 601 includes a tapered inlet flow path 602. Many other shapes are possible.

  FIG. 7 shows a cross-sectional view of a DPI 700 according to another embodiment, with various feature dimensions in millimeters. The DPI 700 can accommodate an actuator having a diameter of about 4.5 to 5.5 millimeters, although other sizes may be used. The DPI 700 includes a mouthpiece 701 having an outlet channel 702. Unlike the outlet channel 402 described above, the outlet channel 702 is not cylindrical and has a cross-sectional area that varies along its length. The chamber portion 703 includes an inlet channel 704 (in this embodiment, tapered) that leads to the chamber 705. Bypass channel 706 directs make-up air to sheath channel 707, and make-up air does not pass through chamber 705.

  While the DPI 700 serves as one embodiment of a possible example, it should be understood that the claimed invention is not limited to the specific dimensions or combinations of features shown. For example, the length of the mouthpiece 701 may be shorter or longer than that shown in FIG. The outlet channel 702 may be cylindrical or have a cross-sectional area that varies along the length of the mouthpiece 701. The two ends of the outlet channel 702 may have the same size, or may have different sizes and one end may be larger than the other. The cylindrical flow path does not have to be a cylindrical cylinder, and may have a polygonal, elliptical, or other cross-sectional shape. The length of the inlet channel 704 can vary, and the inlet channel 704 can be cylindrical or have a cross-sectional area that varies along the length of the inlet channel 704. The inlet channel 704 may be straight, tapered, curved, angled, or have another shape. The bypass channel 706 and the sheath channel 707 may have various shapes or sizes, or may be omitted. For example, the sheath channel 707 may be linear, curved, tapered, angled, or have a different shape. Various numbers of bypass channels 706 can be provided. A plurality of sheath channels 707 may be provided. The length, shape, and cross-sectional area of the chamber 705 can be varied from the dimensions described within any usable range.

  In some embodiments, the ratio of chamber diameter to inlet diameter is 1.5 to 3.0, such as 2.10 to 2.25. In some embodiments, the ratio of the chamber diameter to the diameter of the actuator in the chamber is 1.0 to 2.0, such as 1.3 to 1.6.

  The mouthpiece 701 and chamber portion 703 can be made of any suitable material, but are preferably molded from a medical or food grade polymer, such as polycarbonate, ABS, or other polymers or mixtures of polymers. The DPI 700 components may be reusable or disposable.

The embodiment of FIG. 7 is about 0.059 (cmH ₂ O) ₂ ^. It was measured to have a flow resistance of ⁵ / Lmin- ¹ . Its performance was tested in vitro using a cascade impactor at a volumetric flow rate of 90 Lmin- ¹ corresponding to a pressure drop of approximately 2 kPa through the inhaler. Several drugs were tested and the results are shown in Table 1 below.

  For drug-coated beads of fluticasone propionate and salmeterol xinafoate, the coating was performed by a piezo-assisted coating (PAC) technique. Briefly, 2 mg of micronized drug powder was weighed into a 30 mL scintillation vial containing three 5.2 mm polystyrene beads. The vial was sealed and the lower half was submerged in a sonication bath for 2 minutes. When the vial is placed in a water bath, the energy imparted to the powder by ultrasound aerosolizes a small portion of the powder layer and the powder is continuously aerosolized and then deposited on the bead surface by gravity sedimentation. As a result, a persistent plume was created. Van der Waals interactions can overwhelm other types of forces, including gravity, because the initial drug particle size is small and therefore the mass is negligible. Other types of forces, such as those resulting from electrostatic interactions, physical interactions, capillary interactions, or others, can also contribute to the binding of powder to the actuator. Further information regarding the deposition of the drug on the beads can be found in the co-pending PCT patent application No. PCT / US2010 / 047043 (published as WO 2011/031564), all disclosures of said literature The contents are incorporated herein by reference.

  For fluticasone propionate and salmeterol xinafoate, the drug deposited on each component of the experimental equipment (bead, device, mouthpiece adapter, USP induction port, and cascade impactor stage) was evaluated by high performance liquid chromatography (HPLC). The delivered fine particle fraction was calculated as the ratio of the drug mass collected from stages 2-8 of the cascade impactor to the drug mass released from the device.

In the embodiments described so far, a single chamber is provided for housing a single actuator. A single actuator may have a single powdered drug attached thereto, or a mixture of powdered drugs may be attached to deliver a combination of drugs.

  In another variation, multiple chambers may be provided to accommodate multiple actuators. For example, multiple actuators may be attached with the same drug or agents to deliver a larger dose than delivered from a single actuator, or to deliver a combination of drugs. Different drugs may be attached to the.

  FIG. 8A shows a perspective view of a chamber portion 801 according to another embodiment. The chamber portion 801 includes two chambers 802a and 802b and two inlet channels 803a and 803b. FIG. 8B shows a cross-sectional view of chamber portion 801 with example dimensions attached. The embodiment of FIGS. 8A and 8B can accommodate an actuator having a diameter of about 3.8 to 4.4 millimeters.

  8C and 8D show two alternative arrangements for connecting multiple chambers 802a and 802b to one or more outlet channels. In the embodiment of FIG. 8C, both chambers 802a and 802b are connected to a single outlet channel 804. In the embodiment of FIG. 8D, chambers 802a and 802b are connected to different respective outlet channels 805a and 805b.

Coated with fluticasone and salmeterol (using PAC method) to assess the aerosol performance of the dual chamber device in vitro (using the same inhaler base with different mouthpiece types) The beads were driven into the next generation cascade impactor at 90 L min ⁻¹ (corresponding to a pressure drop of approximately 2 kPa through the device). Drug deposited on each component of the experimental apparatus (beads, device, mouthpiece adapter, USP induction port, and cascade impactor stage) was analyzed by high performance liquid chromatography (mobile phase = methanol and 0.8% (w / v). ) 75:25 mixture of ammonium acetate buffer (pH 5.5; stationary phase = 5 μm C ₁₈ ; detection wavelength = 228 nm). Deliver the fine particle fraction of the delivered dose to the ratio of the drug mass collected from cascade impactor stages 2-8 to the drug mass released from the device (at 90 L min- ¹ ) aerodynamic diameter cutoff (Corresponding to a size of 6.48 μm).

  The performance of the embodiment of FIG. 8C is summarized in Table 2.

The performance of the embodiment of FIG. 8D is summarized in Table 3.

FIG. 9A shows a perspective view of a chamber portion 901 according to another embodiment. Chamber portion 901 includes three chambers 902a, 902b and 902c and three inlet channels. FIG. 9B shows a cross-sectional view of chamber portion 901 with example dimensions attached. In FIG. 9B, only the inlet channel 903a is visible. The embodiment of FIGS. 9A and 9B can accommodate an actuator having a diameter of about 3.2 to 3.8 millimeters.

  FIG. 9C illustrates the use of chamber portion 901 with a mouthpiece having a single outlet channel 904 through which air and medication are fed from all three chambers 902a, 902b and 902c. Of course, it is also conceivable to use a mouthpiece having a separate respective outlet channel for each of the chambers 902a, 902b and 902c.

  The above examples are dual and triple chambers where the overall diameter of the inhaler is kept constant so that the dimensions of the chamber and inlet channel are reduced, and the single chamber embodiment In comparison, a small actuator is required to be used. This is not a requirement. The overall size of the inhaler can be changed as needed.

  While the embodiment of FIGS. 8A-9C serves as an example embodiment that can be implemented, it will be appreciated that the dimensions and combinations of features illustrated are exemplary and numerous variations are possible.

  The above-described embodiments are also configured for oral inhalation of powdered drugs. Devices embodying the invention may be configured for nasal delivery of drugs as an alternative to or in addition to oral delivery. For example, an outlet channel may be included in the nasal adapter.

Cartridge According to another aspect, a cartridge with a pre-loaded actuator is provided. Such a cartridge can contain a single dose of powdered drug and can be loaded into a reusable DPI that operates in accordance with the principles of the present invention.

  FIG. 10 shows a cartridge 1000 according to the embodiment. The cartridge 1000 includes a first outer shell 1001 that defines a first end of the cartridge. The first outer shell 1001 includes a throttle hole 1002 that serves as an inlet channel. The cartridge 1000 further includes a second outer shell 1003 that defines the second end of the cartridge. The second outer shell 1003 further defines at least a portion of the chamber 1004 and includes a retaining element 1005. The holding element 1005 may be a mesh or lattice that extends across the cross-sectional area of the second outer shell 1003. An actuator 1006 with one or more powdered drugs attached is also provided. The first and second outer shells 1001 and 1003 are configured to form a finished cartridge 1000 that engages and surrounds the actuator 1006. The closed ends of the first and second outer shells 1001 and 1003 are formed by first and second pierceable seals 1007 and 1008, which further includes first and second outer shells. The end of the cartridge 1000 is formed when the shells 1001 and 1003 are engaged. Each pierceable seal 1007 and 1008 may be, for example, an aluminum foil or plastic septum that serves to keep contaminants outside the cartridge 1000, but to open the end of the cartridge 1000 for use. It can be easily punctured (as described below). The retention member 1005 has an opening that allows the drug expelled from the actuator 1006 in use to pass through the retention member 1005, but the retention member prevents the actuator 1006 from exiting the cartridge 1000. Thus, the cartridge 1000 contains and protects the actuator and medication until inserted into the inhaler for use. In some embodiments, the cartridge may be used once to administer a single dose of medication.

  The cartridge 1000 can be mass produced and supplied to an inhaler user for treatment of various conditions. FIG. 11 shows an example of a method for manufacturing the cartridge 1000. Several first shells 1001 are manufactured and several actuators 1006 are manufactured and coated with the drug. Actuator 1006 is suspended from string 1101 for convenient handling by automated manufacturing equipment. The actuator 1006 is placed in the first outer shell 1001 and the second outer shell 1003 is engaged with the first outer shell 1001 to form the finished cartridge 1000. In some embodiments, the string 1101 is cut by the action of engaging the first and second outer shells 1001 and 1003 so that the individual cartridges 1000 can be easily separated. Preferably, a portion of the string 1101 remains inside each cartridge 1000 and the actuator 1006 is suspended so that the actuator does not easily contact the cartridge wall.

  The act of loading one of the cartridges 1000 into the inhaler may puncture the seals 1007 and 1008 to prepare for cartridge use. This process is illustrated in FIG. Inhaler first portion 1201 is configured to receive a first end of cartridge 1000. The first portion 1201 includes a lip 1202 and the cartridge 1000 stops on this lip when it is first loaded into the first portion 1201. Thereafter, the second portion 1203 of the inhaler with the second lip 1204 is placed on the cartridge 1000. When the first and second portions 1201 and 1203 are pushed together, the lips 1202 and 1204 puncture the seal at the end of the cartridge 1000 to provide openings 1205 and 1206 for the passage of air. In some embodiments, pushing the inhaler first and second portions 1201 and 1203 together further compresses the cartridge 1000, resulting in the string 1101 being cut and the actuator 1006 being released, Can vibrate during inhalation.

Multi-dose dry powder inhaler According to another aspect, a continuous inhaler is provided. FIG. 13 illustrates a continuous inhaler 1300 according to an embodiment. The continuous inhaler 1300 includes a mouthpiece portion 1301 and a round base portion 1302. A rotary carriage 1303 is disposed within the base 1302 and includes a set of slots 1304 configured to receive a cartridge, eg, a cartridge similar to the cartridge 1000 described above. Each cartridge includes an actuator 1006 to which a powdered medicine is attached.

  FIG. 14 shows the continuous inhaler 1300 after loading. Once the continuous inhaler 1300 has been loaded, the user can rotate the carriage 1303 to place a new cartridge 1000 in alignment with the outlet 1401 and inhale air through the inhaler 1300. In order to take a new medicine, the user repeats the above procedure using another new cartridge 1000.

Performance Example Testing has shown that the device according to embodiments can still deliver drugs effectively even at low air flow rates compared to conventional devices. Table 4 below compares the inhalable fraction of particles produced by DPI embodying the present invention with that produced by a conventional inhaler using lactose carrier particles. Two different drugs commonly prescribed for lung disease, budesonide, a corticosteroid and salbutamol, a beta agonist, were tested at three different flow rates.

The relative insensitivity to flow rates can be difficult to use with conventional inhalers, for example in the treatment of patients with impaired respiratory capacity as a result of chronic obstructive pulmonary disease (COPD). It can be particularly important.

  Tests have also shown that DPIs embodying the invention can be provided with a wide variety of drug coatings at doses comparable to those delivered by conventional commercial inhalers. These doses range from low doses (eg, 12 μg formoterol delivered by Foradil® Aerolyzer, and 22 μg tiotropium bromide delivered by Spiriva® Handihaler®) to high doses (eg, Pulmicort). Up to 200 μg budesonide delivered from the (registered trademark) Turbohaler® DPI, or 500 μg fluticasone delivered by the Advair® Diskus® DPI).

  In another comparative study, the performance of the dual chamber DPI embodying the present invention was compared to the performance of a conventional commercial inhaler of different design in the dosing of two different drugs: fluticasone propionate and salmeterol xinafoate. It was. Each of the two actuators of the DPI embodying the present invention retained one of two drugs. The test results are shown in Tables 5A and 5B below. Table 5A lists the results for conventional commercial inhalers and Table 5B lists the results for DPIs embodying the present invention.

In Tables 5A and 5B, the values for the release fraction (EF), fine particle fraction (FPF), inhalable fraction (RF), and fine particle dose (FPD) were determined in vitro for both inhalers. For conventional commercial inhalers, EF and RF are presented as a percentage of the labeled dose. All values are shown as the mean (± standard deviation) of 3 replicate measurements. As is apparent, the DPI embodying the present invention provides significantly higher drug delivery and delivers significant amounts of drug even at low flow rates. The relatively low value of FPF achieved with conventional commercial inhalers is that a significant portion of the powdered drug remains attached to the carrier particles used in the system and is not possible with inhalable particle sizes. It is thought to be due to the fact that it did not come. In contrast, in the DPI embodying the present invention, only a powdered drug without carrier particles comes out of the DPI, so a much larger percentage of the drug released is inhalable.

  In another comparative study, two adult volunteer subjects were re-enrolled from a subject cohort who participated in the safety study of tacrolimus inhalation with nebulization therapy (5 mg). The peak concentration of tacrolimus in blood after 1 hour inhalation in subjects exposed to the drug by nebulization therapy ranged from 5 to 8 ng / ml. In this study, subjects inhaled tacrolimus via DPI embodying the invention or standard HandiHaler DPI on study day 1 or 8, respectively. Tacrolimus concentration was measured from blood samples 1 hour after inhalation. The results of this study are summarized in Table 6 below.

Of course, any possible combination of any of the features described herein may be considered disclosed. The present invention has been described in detail herein for purposes of clarity and understanding. However, one of ordinary skill in the art appreciates that certain changes and modifications may be practiced within the scope of the appended claims.

Claims (31)

A dry powder inhaler,
An inlet channel through which air enters the inhaler;
A chamber that receives air from the inlet channel and is sized and shaped to include a single actuator having a powdered drug attached thereto;
A holding member disposed at the end of the chamber opposite the inlet channel, which allows air and powdered drug to pass through the holding member and allows an actuator to pass through the holding member; a holding member having one or more openings formed in size to prevent,
An outlet channel for air and powdered medication exiting the inhaler to be delivered to the patient;
The chamber has a longitudinal axis, the inlet channel is substantially coaxial with the longitudinal axis, and the outlet channel is substantially coaxial with the longitudinal axis of the chamber;
The inhaler geometry is such that a flow profile is generated inside the chamber that repeatedly vibrates the single actuator substantially coaxially with the longitudinal axis, and the repeated vibration causes the powdered drug to flow through the actuator. A dry powder inhaler that is detached from the surface, entrained in air, and delivered to a patient through an outlet channel.   The dry powder inhaler of claim 1, wherein the cross-sectional area of the flow path through the inhaler is increased by one step at the chamber inlet.   3. A dry powder inhaler according to claim 2, wherein at the inlet of the chamber, the diameter of the chamber is at least 1.5 times the diameter of the inlet channel.   The dry powder inhaler of claim 1, wherein the inlet flow path comprises a tapered tube.   The dry powder inhaler according to claim 1, wherein the outlet channel comprises a tube whose cross-sectional area varies along its length.   The dry powder inhaler according to claim 1, wherein the outlet channel is included in a mouthpiece adapted to be placed in a patient's mouth.   The dry powder inhaler of claim 1, wherein the outlet channel is included in a nasal adapter adapted to fit a patient's nostril.   The dry powder inhaler of claim 1, further comprising one or more bypass channels that receive makeup air from outside the inhaler and deliver the makeup air to the patient without passing through the chamber.   The dry powder inhaler according to claim 1, wherein the inlet channel is a first inlet channel and the chamber is a first chamber, and the dry powder inhaler further comprises a second inlet channel and a second chamber. vessel.   10. A dry powder inhaler according to claim 9, wherein air and powdered medicament exiting the first and second chambers are delivered to the outlet channel.   The outlet channel is a first outlet channel, the dry powder inhaler further comprises a second outlet channel, air and powdered medicament exiting the first chamber are delivered to the first outlet channel; and The dry powder inhaler of claim 9, wherein air and powdered drug exiting the second chamber are delivered to the second outlet channel.   The dry powder inhaler of claim 9, wherein the first and second chambers are of the same size.   The dry powder inhaler of claim 1, wherein the dry powder inhaler is separable so that a capsule containing the actuator can be inserted into the chamber.   14. A dry powder inhaler according to claim 13, further comprising a mechanism for piercing the seal at the capsule end.   The dry powder inhaler of claim 1, wherein the air flow through the inhaler is driven by the patient's inspiratory effort.   2. A dry powder inhaler according to claim 1 in combination with an actuator.   17. A dry powder inhaler according to claim 16, wherein the actuator is made of expanded polystyrene. Actuator has a density 0.001~0.50g / cm ^3, a dry powder inhaler of claim 16. 17. A dry powder inhaler according to claim 16, wherein the actuator has a diameter of at least 1000 μm . 17. A dry powder inhaler according to claim 16, wherein the actuator has a diameter of 1000 to 6000 [ mu ] m.   17. A dry powder inhaler according to claim 16, wherein the actuator has a mass of 0.1 to 5.0 milligrams.   17. A dry powder inhaler according to claim 16, wherein the actuator has a mass of 0.5 to 2.5 milligrams.   17. A dry powder inhaler according to claim 16, wherein the combination of drugs is attached to the actuator.   The plurality of chambers comprising the plurality of chambers disposed on a rotating element for selectively aligning any of the chambers with the outlet flow path. Dry powder inhaler. A dry powder inhaler comprising an inlet channel, a chamber, and an outlet channel, wherein the chamber has a longitudinal axis, the inlet channel is substantially coaxial with the longitudinal axis, and the chamber is a single unit houses the actuator, one or more powdered medicament is caused to adhere to the outer surface of the actuator, obtaining a dry powder inhaler;
Suction is performed through the outlet passage is substantially coaxial with the longitudinal axis, causes air to flow into the inlet flow path, passed through a chamber, and by passing through the exit chamber, further actuator said longitudinal by the air stream A method comprising the step of repeatedly oscillating substantially coaxially with the shaft so that the powdered drug is easily expelled from the surface of the actuator and is entrained in an air stream and conveyed through an outlet channel. And separating the inhaler portion comprising portion and an outlet flow passage of the inhaler comprising a chamber,
Loading an actuator into the chamber;
26. The method of claim 25, further comprising reengaging a portion of the inhaler comprising a chamber and a portion of the inhaler comprising an outlet flow path .   26. The method of claim 25, wherein the powdered drug combination is deposited on the actuator. Dry powder inhaler comprises at least two chambers, each accommodating a single actuator which drug has been allowed to adhere, air flow facilitates the powdered medicament to be inhaled by vibrating each actuator expel the method of claim 25. 29. The method of claim 28, wherein each actuator has the same powdered drug attached thereto. 29. The method of claim 28, wherein each actuator is provided with a different powdered drug.   A dry powder inhaler,
  An inlet channel through which air enters the inhaler;
  A chamber for receiving air from the inlet channel, the chamber being sized and shaped to include a single actuator;
  A holding member disposed at the end of the chamber opposite the inlet channel, which allows air and powder to pass through the holding member and prevents the actuator from passing through the holding member A holding member having one or more openings formed in
  An outlet channel through which air and powder exit the inhaler to be delivered to the patient;
Comprising
  The chamber has a longitudinal axis, the inlet channel is substantially coaxial with the longitudinal axis, and the outlet channel is substantially coaxial with the longitudinal axis of the chamber;
  The inhaler geometry is such that a flow profile is generated inside the chamber that repeatedly vibrates the single actuator substantially coaxially with the longitudinal axis, and the repeated vibration causes the powder to pass through the outlet channel to the patient. A dry powder inhaler that is to be delivered.